Huntington's Disease Repeat Instability and Pathogenesis

Summary

Principal Investigator: Vanessa Wheeler
Affiliation: Harvard University
Country: USA
Abstract: Huntington's disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a polymorphic CAG repeat tract beyond a threshold of ~ 36 units. The expanded CAG repeat is translated into a polyglutamine stretch at the amino-terminus of the huntingtin protein, triggering cell death in a subset of neurons in the striatum and cortex. The expanded CAG repeat also exhibits dramatic instability in the germline and in somatic tissues. The long-term goals of this research are to elucidate the molecular pathways that underlie the instability of the HD CAG repeat and the specific neurodegeneration triggered by mutant huntingtin. In HD knock-in mice, which accurately recapitulate the human HD mutation, the Msh2 gene is a modifier of repeat instability and an early striatal phenotype. In this study we will test the hypothesis that Msh2 acts in the mismatch repair pathway to modify CAG repeat instability and early phenotypes in HD knock-in mice. We will perform genetic crosses with mice deficient in specific mismatch repair genes and mouse line carrying a mutation in Msh2's ATPase domain. These experiments will provide mechanistic insight into Msh2's role in CAG repeat instability and phenotypic expression of the mutant HD allele. To determine whether candidate DMA repair genes are modifiers of the age of onset of HD in humans genetic association studies will be performed using 'extreme'individuals with onset ages deviating from values predicted by CAG repeat size. To gain further insight into the mechanism by which Msh2 modifies repeat instability and early striatal disease in the mouse we will generate a conditional knockout of the Msh2 gene using the Cre-loxP system. We will specifically inactivate Msh2 in forebrain neurons using a Camklla- driven Cre transgene to test the hypothesis that Msh2 acts in striatal neurons to modify instability and early phenotypes. Together, these studies will provide insight into mechanisms of repeat instability and pathogenesis, leading to rational therapeutic strategies aimed at slowing or halting this devastating disease.
Funding Period: 2005-09-01 - 2010-08-31
more information: NIH RePORT

Top Publications

  1. pmc HD CAGnome: a search tool for huntingtin CAG repeat length-correlated genes
    Ekaterina I Galkina
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America
    PLoS ONE 9:e95556. 2014
  2. pmc A broad phenotypic screen identifies novel phenotypes driven by a single mutant allele in Huntington's disease CAG knock-in mice
    Sabine M Holter
    German Mouse Clinic, Institute of Developmental Genetics, Helmholtz Zentrum Munchen, Neuherberg Munich, Germany
    PLoS ONE 8:e80923. 2013
  3. pmc Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome-wide and candidate approaches
    Ricardo Mouro Pinto
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America
    PLoS Genet 9:e1003930. 2013
  4. pmc Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington's disease knock-in mice
    Marina Kovalenko
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America
    PLoS ONE 7:e44273. 2012
  5. pmc Large-scale phenotyping of an accurate genetic mouse model of JNCL identifies novel early pathology outside the central nervous system
    John F Staropoli
    Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America
    PLoS ONE 7:e38310. 2012
  6. pmc Early alterations of brain cellular energy homeostasis in Huntington disease models
    Fanny Mochel
    INSERM UMR S975 and Assistance Publique des Hôpitaux de Paris, Department of Genetics, Hopital La Salpetriere, 75013 Paris, France
    J Biol Chem 287:1361-70. 2012
  7. pmc Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver
    Jong Min Lee
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America
    PLoS ONE 6:e23647. 2011
  8. pmc Differential effects of the Huntington's disease CAG mutation in striatum and cerebellum are quantitative not qualitative
    Elisa Fossale
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
    Hum Mol Genet 20:4258-67. 2011
  9. pmc A novel approach to investigate tissue-specific trinucleotide repeat instability
    Jong Min Lee
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
    BMC Syst Biol 4:29. 2010
  10. pmc Stoichiometry of base excision repair proteins correlates with increased somatic CAG instability in striatum over cerebellum in Huntington's disease transgenic mice
    Agathi Vassiliki Goula
    Department of Neurobiology and Genetics, Institute of Genetics and Molecular and Cellular Biology, UMR 7104 CNRS INSERM UdS, Illkirch, France
    PLoS Genet 5:e1000749. 2009

Scientific Experts

  • Jong Min Lee
  • F Mochel
  • Vanessa Wheeler
  • Tammy Gillis
  • Marcy E MacDonald
  • Ella Dragileva
  • Edith Lopez
  • Sabine M Holter
  • Marina Kovalenko
  • James F Gusella
  • Elisa Fossale
  • Audrey E Hendricks
  • Alejandro Lloret
  • Richard H Myers
  • Ekaterina I Galkina
  • Ricardo Mouro Pinto
  • Kathryn R Coser
  • Lore Becker
  • Toshi Shioda
  • Martin Klingenspor
  • Jolene R Guide
  • Thomas Klopstock
  • Jolene Guide
  • Lillian Garrett
  • Isaac S Kohane
  • Valerie Gailus-Durner
  • Birgit Rathkolb
  • Jason St Claire
  • Helmut Fuchs
  • Martin Hrabe de Angelis
  • Jan Rozman
  • Eckhard Wolf
  • Ihn Sik Seong
  • John F Staropoli
  • Raju Kucherlapati
  • Meera Swami
  • Kathryn L Lunetta
  • Agathi Vassiliki Goula
  • Allison Teed
  • Aram Shin
  • Jonathan Seidman
  • Guo Min Li
  • Susan Cotman
  • Wolfgang Wursta
  • Anja Schrewed
  • Christopher E Pearson
  • Hiroko Wakimoto
  • Mary Stromberg
  • Holger Schulz
  • Kim Holloway
  • Lisa Glasl
  • Mark J Daly
  • Gagan B Panigrahi
  • Wolfgang Hans
  • Alexander Götz
  • Andrew Kirby
  • Paula E Cohen
  • Caixia Hou
  • Rose Mary Boustany
  • Julia Calzada-Wack
  • Wolfgang Wurst
  • Sylvie Breton
  • Hualing Dong
  • Evan Gale
  • Klaus Ruether
  • Sergej Skosyrski
  • Daniela S Krause
  • Hayat Harati
  • Susan L Cotman
  • Eric Hill
  • Michelle E Ehrlich
  • Thure Adler
  • Andreas Zimmer
  • Jaclyn New
  • Minxuan Sun
  • Ildiko Racz
  • Patricia Da Silva-Buttkus
  • Jack Favor
  • Raffi Bekeredjian
  • Sunita Biswas
  • Dirk H Busch
  • Frauke Neff
  • Oliver Puk
  • Melanie H Kucherlapati
  • Anja Schrewe
  • Jochen Graw
  • Larissa Haliw
  • Diane E Brown
  • Yvon Trottier
  • Edith T Lopez

Detail Information

Publications15

  1. pmc HD CAGnome: a search tool for huntingtin CAG repeat length-correlated genes
    Ekaterina I Galkina
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America
    PLoS ONE 9:e95556. 2014
    ..However, a potentially more powerful approach is a continuous analysis strategy that takes advantage of all of the different CAG lengths, to capture effects that are expected to be critical to HD pathogenesis...
  2. pmc A broad phenotypic screen identifies novel phenotypes driven by a single mutant allele in Huntington's disease CAG knock-in mice
    Sabine M Holter
    German Mouse Clinic, Institute of Developmental Genetics, Helmholtz Zentrum Munchen, Neuherberg Munich, Germany
    PLoS ONE 8:e80923. 2013
    ..These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing. ..
  3. pmc Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome-wide and candidate approaches
    Ricardo Mouro Pinto
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America
    PLoS Genet 9:e1003930. 2013
    ....
  4. pmc Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington's disease knock-in mice
    Marina Kovalenko
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America
    PLoS ONE 7:e44273. 2012
    ....
  5. pmc Large-scale phenotyping of an accurate genetic mouse model of JNCL identifies novel early pathology outside the central nervous system
    John F Staropoli
    Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America
    PLoS ONE 7:e38310. 2012
    ..These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3(Δ) (ex7/8) mice that merit further study for JNCL biomarker development...
  6. pmc Early alterations of brain cellular energy homeostasis in Huntington disease models
    Fanny Mochel
    INSERM UMR S975 and Assistance Publique des Hôpitaux de Paris, Department of Genetics, Hopital La Salpetriere, 75013 Paris, France
    J Biol Chem 287:1361-70. 2012
    ....
  7. pmc Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver
    Jong Min Lee
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America
    PLoS ONE 6:e23647. 2011
    ..Investigation of the dynamics of the CAG repeat size changes over time may provide insights into the mechanisms underlying CAG repeat instability...
  8. pmc Differential effects of the Huntington's disease CAG mutation in striatum and cerebellum are quantitative not qualitative
    Elisa Fossale
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
    Hum Mol Genet 20:4258-67. 2011
    ....
  9. pmc A novel approach to investigate tissue-specific trinucleotide repeat instability
    Jong Min Lee
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
    BMC Syst Biol 4:29. 2010
    ..However progress in this area has been hampered by the lack of sensitive high-throughput instability quantification methods and global approaches to identify the underlying factors...
  10. pmc Stoichiometry of base excision repair proteins correlates with increased somatic CAG instability in striatum over cerebellum in Huntington's disease transgenic mice
    Agathi Vassiliki Goula
    Department of Neurobiology and Genetics, Institute of Genetics and Molecular and Cellular Biology, UMR 7104 CNRS INSERM UdS, Illkirch, France
    PLoS Genet 5:e1000749. 2009
    ..We propose that the stoichiometry of BER enzymes is one critical factor underlying the tissue selectivity of somatic CAG expansion...
  11. pmc Estimating the probability of de novo HD cases from transmissions of expanded penetrant CAG alleles in the Huntington disease gene from male carriers of high normal alleles (27-35 CAG)
    Audrey E Hendricks
    Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA
    Am J Med Genet A 149:1375-81. 2009
    ..These estimates may be useful in genetic counseling for male high normal allele carriers...
  12. pmc Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset
    Meera Swami
    Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
    Hum Mol Genet 18:3039-47. 2009
    ....
  13. pmc Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes
    Ella Dragileva
    Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston MA 02114, USA
    Neurobiol Dis 33:37-47. 2009
    ....
  14. pmc Factors associated with HD CAG repeat instability in Huntington disease
    V C Wheeler
    Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
    J Med Genet 44:695-701. 2007
    ..The instability of the HD disease allele in male intergenerational transmissions is reflected in the variability of the CAG repeat in DNA from the sperm of male carriers of the HD gene...
  15. ncbi Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington's disease knock-in mice
    Alejandro Lloret
    Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
    Hum Mol Genet 15:2015-24. 2006
    ..Our findings set the stage for defining disease-related genetic pathways that will ultimately provide insight into disease mechanism...